Acute respiratory distress syndrome (ARDS) is a life-threatening condition that affects over 150,000 Americans annually. ARDS-associated mortality (~ 30%) is reduced by limiting tidal lung expansion during mechanical ventilation. Lung expansion reflects transpulmonary pressure (PL), the difference between pressures at the airway opening and pleural space (PL = Pao - Ppl). Mechanical ventilator settings that cause PL values to be either too high at end-inflation or too low at end-exhalation (ee) can result in ventilator-induced lung injury (VILI), even when tidal volume is limited. To avoid VILI, clinicians limit tidal volume and monitor Pao as an index of lung expansion. This strategy is effective to the extent that Ppl is predictable and/or restricted to a narrow range. However, there is strong evidence to suggest that Ppl at ee ranges widely among patients with ARDS due to chest wall factors such as obesity and abdominal fluid accumulation. Therefore, use of Pao alone to guide ventilator pressure settings without knowledge of Ppl is risky, since high Ppl relative to Pao could cause underinflation at ee and increase risk of VILI. We hypothesize that many patients with ARDS have high Ppl and low PL at ee, exacerbating VILI. We further hypothesize that mechanical ventilation managed by reference to PL, estimated using esophageal pressure (Pes), is superior to ventilator management by Pao without reference to PL. We test these hypotheses in 3 Specific Aims. Aim 1 - Anesthetized morbidly obese subjects with healthy lungs. We will test the validity of Pes as an indicator of Ppl by measuring Pes and the Pao needed to reinflate the lungs from relaxation (closing) volume. Aim 2 - Patients with ARDS on mechanical ventilation. We expect that Pes (and gastric pressure) will range widely among patients, and predict that patients with higher Pes and lower PL at ee will exhibit more impaired gas exchange suggestive of shunt and more non-uniform aeration of lungs on CT scan during tidal ventilation. Aim 3 - Prospective randomized trial in patients with ARDS. We will test the hypothesis that adjusting ventilator pressure to achieve appropriate PL values (as opposed to Pao) will improve gas exchange, reduce the release of proinflammatory cytokines considered indicative of VILI, and reduce the fraction of non-aerated or poorly aerated lung at ee on CT scan. Results of these studies may suggest changes in the management of mechanical ventilation that will improve outcome in ARDS.